Efforts are focused on the design, synthesis and evaluation of polypeptides andconformationally constrained peptidomimetics that are targeted to inhibit, orotherwise modulate key cellular signal transduction processes. Our goal is todevelop therapeutic agents that are selective in inhibiting the oncogenic cellproliferative signal, or to boost the effectiveness of tumor suppressor genes.Our major research area is concerned with developing inhibitors of the rasoncogenic signaling pathway at the c-erbB2 growth factor receptor interactionsite with the Grb2 adaptor protein. Based on a phage library based cyclicprototype peptide, we developed several redox-stable analogs that boundselectively to the Grb2-SH2 domain protein at high nanomolar concentrations.Significantly, these agents inhibited the growth factor receptor associationin cell homogenates of breast cancer cells. Cell permeabilized analogs alsoinhibited MAP kinase activation in intact cancer cells. These novel inhibitorsare non-phosphorylated and do not contain phosphate mimicking groups, and areexpected to be constitutively active in cells. Inactivation of the c-erbB2receptor initiated signaling has potential therapeutic applications, mostnotably in the management of breast cancer.Good progress has been made in several related project areas. These include: 1./ Studies on the mechanism of action of the active site segments of Cdkinhibitory proteins, p21(Waf1/Cip1) and p16(INK4A); 2./ design of cyclicconformationally rigid peptides that inhibit Matriptase, an epithelial cellsurface derived matrix protease that has a potential function in breast cancercell metastasis; and 3./ development of proteolytically stable peptide analogsthat serve as novel HIV integrase enzyme inhibitors, as model compounds foranti-HIV therapeutics design. - antiproliferative agents, cell cycle inhibitors, peptide conformation, peptide synthesis, peptides, SH2 domain, Signal Transduction, peptidomimetics, - Neither Human Subjects nor Human Tissues